UT Pathologists Believe They Have Pinpointed Achilles Heel of HIV

July 16, 2008

Human Immunodeficiency Virus (HIV) researchers at The University of Texas Medical School at Houston believe they have uncovered the Achilles heel in the armor of the virus that continues to kill millions.

The weak spot is hidden in the HIV envelope protein gp120. This protein is essential for HIV attachment to host cells, which initiate infection and eventually lead to Acquired Immunodeficiency Syndrome or AIDS. Normally the body's immune defenses can ward off viruses by making proteins called antibodies that bind the virus. However, HIV is a constantly changing and mutating virus, and the antibodies produced after infection do not control disease progression to AIDS. For the same reason, no HIV preventative vaccine that stimulates production of protective antibodies is available.

The Achilles heel, a tiny stretch of amino acids numbered 421-433 on gp120, is now under study as a target for therapeutic intervention. Sudhir Paul, Ph.D., pathology professor in the UT Medical School, said, "Unlike the changeable regions of its envelope, HIV needs at least one region that must remain constant to attach to cells. If this region changes, HIV cannot infect cells. Equally important, HIV does not want this constant region to provoke the body's defense system. So, HIV uses the same constant cellular attachment site to silence B lymphocytes - the antibody producing cells. The result is that the body is fooled into making abundant antibodies to the changeable regions of HIV but not to its cellular attachment site. Immunologists call such regions superantigens. HIV's cleverness is unmatched. No other virus uses this trick to evade the body's defenses."

Paul is the senior author on a paper about this theory in a June issue of the journal Autoimmunity Reviews. Additional data supporting the theory are to be presented at the XVII International AIDS Conference Aug. 3-8 in Mexico City in two studies titled "Survivors of HIV infection produce potent, broadly neutralizing IgAs directed to the superantigenic region of the gp120 CD4 binding site" and "Prospective clinical utility and evolutionary implication of broadly neutralizing antibody fragments to HIV gp120 superantigenic epitope."

First reported in the early 1980s, HIV has spread across the world, particularly in developing countries. In 2007, 33 million people were living with AIDS, according to a report by the World Health Organization and the United Nations.

Paul's group has engineered antibodies with enzymatic activity, also known as abzymes, which can attack the Achilles heel of the virus in a precise way. "The abzymes recognize essentially all of the diverse HIV forms found across the world. This solves the problem of HIV changeability. The next step is to confirm our theory in human clinical trials," Paul said.

"The work of Dr. Paul's group is highly innovative. They have identified antibodies that, instead of passively binding to the target molecule, are able to fragment it and destroy its function. Their recent work indicates that naturally occurring catalytic antibodies, particularly those of the IgA subtype, may be useful in the treatment and prevention of HIV infection," said Steven J. Norris, Ph.D., holder of the Robert Greer Professorship in the Biomedical Sciences and vice chair for research in the Department of Pathology and Laboratory Medicine at the UT Medical School at Houston.

The abzymes are derived from HIV negative people with the autoimmune disease lupus and a small number of HIV positive people who do not require treatment and do not get AIDS. Stephanie Planque, lead author and UT Medical School at Houston graduate student, said, "We discovered that disturbed immunological events in lupus patients can generate abzymes to the Achilles heel of HIV. The human genome has accumulated over millions of years of evolution a lot of viral fragments called endogenous retroviral sequences. These endogenous retroviral sequences are overproduced in people with lupus, and an immune response to such a sequence that resembles the Achilles heel can explain the production of abzymes in lupus. A small minority of HIV positive people also start producing the abzymes after decades of the infection. The immune system in some people can cope with HIV after all."

Carl Hanson, Ph.D., who heads the Retrovirus Diagnostic Section of the Viral and Rickettsial Disease Laboratory of the California Department of Public Health, has shown that the abzymes neutralize infection of human blood cells by diverse strains of HIV from various parts of the world. Human blood cells are the only cells that HIV infects.

"This is an entirely new finding. It is a novel antibody that appears to be very effective in killing the HIV virus. The main question now is if this can be applied to developing vaccine and possibly used as a microbicide to prevent sexual transmission," said David C. Montefiori, Ph.D., director of the Laboratory for AIDS Vaccine Research & Development at Duke University Medical Center. The abzymes are now under development for HIV immunotherapy by infusion into blood. They could also be used to guard against sexual HIV transmission as topical vaginal or rectal formulations.

"HIV is an international priority because we have no defense against it," Paul said. "Left unchecked, it will likely evolve into even more virulent forms. We have learned a lot from this research about how to induce the production of the protective abzymes on demand. This is the Holy Grail of HIV research -- development of a preventative HIV vaccine."

Major contributors to the research from the UT Medical School include Yasuhiro Nishiyama, Ph.D., and Hiroaki Taguchi, Ph.D., both with the Department of Pathology and Laboratory Medicine, and Miguel Escobar, M.D., of the Department of Pediatrics. Maria Salas and Hanson, both with the Viral and Rickettsial Disease Laboratory, contributed.

The journal article is titled "Catalytic antibodies to HIV: Physiological role and potential clinical utility". The research was funded by the National Institutes of Health and the Texas Higher Education Coordinating Board.

This book introduces the reader to the theory of catalytic gene therapy–the premise that it is possible to correct the DNA sequences that cause genetic diseases through the use of catalytic antibodies, also known as abzymes. The basic theory of catalysis and antibody structure and function are discussed first, followed by a short discussion of abzymes. The abzyme used to insert an oligomer, coined an integrase abzyme, it is suggested, can be produced by immunizing with a transition state analog for the insertion reaction, whose tentative structure is given in the text. Cystic fibrosis is used as a model system for the application of catalytic gene therapy. Aspects of systemic lupus erythematosus are also discussed as they provide additional clues as to how catalytic gene therapy could...

This comprehensive three-volume set is the standard reference in the field of organic synthesis, catalysis and biocatalysis. Edited by a highly experienced and highly knowledgeable team with a tremendous amount of experience in this field and its applications, this edition retains the successful concept of past editions, while the contents are very much focused on new developments in the field. All the techniques described are directly transferable from the lab to the industrial scale, making for a very application-oriented approach. A must for all chemists and biotechnologists.

Antioxidant Polymers is an exhaustive overview of the recent developments in the field of polymeric materials showing antioxidant properties. This research area has grown rapidly in the last decade because antioxidant polymers have wide industry applications ranging from materials science to biomedical, pharmaceuticals and cosmetics.

An authoritative review of modern sensor technology-essential information for analytical chemists, biochemists, biotechnologists, spectroscopists, and chemical engineers As sensors begin to realize their commercial and practical potential in fields ranging from the automobile and semiconductor industries to environmental monitoring and clinical diagnostics, this timely work offers an important survey of the principles, construction, and applications of the most popular types of chemical and biological sensors in use today. Principles of Chemical and Biological Sensors brings together a wealth of valuable material in a single source, providing scientists and researchers with a basic grasp of the latest developments in this area, as well as information on trends and future directions....

Monoclonal antibodies are antibody molecules having homogeneous structure and known specificity. This book provides a basic and overall idea of research carried out in the field of monoclonals for the past three decades. This book discusses in detail the production of monoclonal antibodies, the techniques used to make human monoclonals, the wide applications of monoclonals in various fields like medical, environmental, industrial and research and the FDA-approved monoclonal drugs with respect to their nature, their modes of action, and the experiments undertaken during their clinical trials, with appropriate diagrams and graphic illustrations. The book also discusses the research undertaken by various biotech companies, patents applied, and the present and future status of monoclonals in...

Exploiting the inherent combinatorial mechanism in the biosynthesis of antibodies, an almost limitless variety of biocatalysts may be generated. Catalytic antibodies are capable of performing almost any type of reaction with high selectivity and stereospecificity. Here, the pioneers in the use of catalytic antibodies review the entire scope of this interdisciplinary field, covering such topics as: * theoretical aspects of structure, mechanism and kinetics * practical considerations, from immunization techniques to screening methods * in vitro evolution and other modern approaches * applications from organic synthesis to medical uses. Backed by the leading authorities in antibody catalysis, this is the first book to provide such comprehensive coverage and will be the prime reference for...

Selenium has a long history of association with human health and disease. This essential trace element exerts its important biological role in selenoproteins. "Selenoproteins and Mimics" presents the latest developments in selenoproteins, their functional imitation by biomimetic chemistry and biology, and their relationship with human health and diseases. This book provides both the basic biology and biochemistry knowledge of selenoproteins, and sophisticated approaches for the development of new selenoprotein mimics. It's a valuable reference for researchers in biological technology, chemical syntheses, and medicine design. Junqiu Liu is a professor at the State Key Lab of Supramolecular Structure and Materials, Jilin University, China. Guimin Luo is a professor at the Key Lab of...

This comprehensive collection of recently developed methods for producing new antibody reagents by immunization and recombinant DNA techniques contains ready-to-use protocols that illuminate current areas of research on antibody structure, functions, and applications. The methods can be applied in basic immunological studies involving antibody specificity, catalysis, and evolution, and in the isolation of rare antibodies by phage display technology and the engineering of new antibodies by mutagenesis. They offer insight into new ways of developing clinically useful antibody reagents.

The objective of the serial is to present considered reviews on the quantitative study of organic compounds and their behavior--physical organic chemistry in its broadest sense--in a manner accessible to a general readership.